PT686. Dextromethorphan-induced serotonin syndrome is via up-regulation of 5-HT1A receptors.

s | 49 maze, and motor coordination by rotarod after caffeine administration for 7 days. Water maze performance by measuring the latency to reach the platform was significantly better in the group of mice receiving moderate dose of caffeine (30.4 ± 7.3 s) compared to the control group latency (63.6 ± 9.4 s, ANOVA test, p˂ 0.05) and the high dose group latency (76.9 ± 8.5 s, ANOVA test, p˂ 0.05). Statistical analysis showed also a significant difference between the control group and the high dose group. Rota rod results showed that the mice of the moderate dose group could stay more time on the rotating rod before they fall (40.5 ± 4.3 s, ANOVA test, p˂ 0.05) than the control group (29.9 ± 2.8 s) and the high dose group (25.2 ± 2.6 s). We concluded that acute administration of moderate dose of caffeine to mice can enhance their spatial memory and motor coordination. However, high dose would have opposite effect and affects negatively in their performance for spatial memory and motor coordination. PT684 Treatment with rapamycin improves deficits of social interaction in the mice exposed in utero to valproic acid Hiroko Murakami-Kotajima, Kazutaka Ikeda, Shigeo Uchino Tokyo Metropolitan Institute of Medical Science Abstract Valproic acid (VPA) is widely used as an anticonvulsant and mood-stabilizing drug. However, since the prenatal exposure of VPA shows increased incidence of autism spectrum disorder (ASD), the administration of VPA in the pregnancy period is forbidden. In contrast, rodent pups exposed in utero to VPA have been used as an animal model of ASD. Recently, decreased or increased mammalian target of rapamycin (mTOR) signaling pathway was shown in VPA-exposed rodents (Nicolini et al., 2015, Qin et al., 2015). The mTOR signaling pathway regulates neuronal cell proliferation, migration and maturation, including synaptogenesis, and overactivation of the mTOR signaling has been implicated in the pathogenesis of particular forms of syndromic ASDs, such as tuberous sclerosis complex (TSC), neurofibromatosis 1, and fragile X syndrome. Treatment with rapamycin, mTOR complex 1 inhibitors, in a mouse model of TSC improved abnormal behaviors, including cognition and sociability. In this study, we investigated the effect of rapamycin on social deficits of ASD model mice exposed in utero to VPA.Valproic acid (VPA) is widely used as an anticonvulsant and mood-stabilizing drug. However, since the prenatal exposure of VPA shows increased incidence of autism spectrum disorder (ASD), the administration of VPA in the pregnancy period is forbidden. In contrast, rodent pups exposed in utero to VPA have been used as an animal model of ASD. Recently, decreased or increased mammalian target of rapamycin (mTOR) signaling pathway was shown in VPA-exposed rodents (Nicolini et al., 2015, Qin et al., 2015). The mTOR signaling pathway regulates neuronal cell proliferation, migration and maturation, including synaptogenesis, and overactivation of the mTOR signaling has been implicated in the pathogenesis of particular forms of syndromic ASDs, such as tuberous sclerosis complex (TSC), neurofibromatosis 1, and fragile X syndrome. Treatment with rapamycin, mTOR complex 1 inhibitors, in a mouse model of TSC improved abnormal behaviors, including cognition and sociability. In this study, we investigated the effect of rapamycin on social deficits of ASD model mice exposed in utero to VPA. We subcutaneously injected VPA at a dose of 600 mg/kg body weight (B.W.) into pregnant mice on gestational day 12.5, and the pups were injected intraperitoneally with rapamycin (10 mg/ kg B.W.) or an equal volume of vehicle once daily for 2 consecutive days. Social interaction test was performed at 24 h after the last administration of rapamycin in 5–6 week-old mice (adolescence) or 10–11 week-old mice (young adult). The administration of rapamycin showed improvement in the social deficits in both adolescence and young adult mice compared with the saline injected control mice. These results suggest that rapamycin has potential to provide an effective treatment for adolescent and young adult patients with not only particular syndromic ASD but also non-syndromic ASD. PT685 Social experience changes remyelination through interleukin-6 in mice Manabu Makinodan1, Daisuke Ikawa1, Toshifumi Kishimoto1, Takashi Komori1, Yuki Miyamoto2, Yosuke Nishihata1, Kosuke Okazaki1, Kazuhiko Yamamuro1, Junji Yamauchi1, Takahira Yamauchi1 1Nara Medical University, Japan, 2National Research Institute for Child Health and Development, Japan Abstract Accumulating findings have shown that psychosocial stress is implicated in the pathobiology of multiple sclerosis. Most of studies regarding psychosocial stress have focused on the onset or relapse of the symptoms, aiming to examine the effects on the “demyelination”. In this study, we sought to investigate whether psychosocial stress affects remyelination, not demyelination since our previous study indicated that psychosocial stress substantially changes myelination only during myelin-developing phase. In order to accomplish this, myelin in the medial prefrontal cortex (mPFC) was depleted with cuprizone and the effects of subsequent social experience on remyelination were evaluated. Interestingly, myelination in the mPFC were severely impaired in socially isolated mice after myelin depletion. We also found that social isolation for 4 weeks increased the levels of interleukin-6 (IL-6) in the mPFC. Moreover, insufficient remyelination in the mPFC of socially isolated mice after myelin-depletion was improved by the administration of IL-6 inhibitor. To validate of the effects of IL-6 on myelination, we performed a neuron-oligodendrocyte co-culture and found that IL-6 treatment markedly interfered with myelination. This study, for the first time, provided direct evidence that social experience is associated with the extent of remyelination through IL-6 expression in mice. Together, these findings suggest that psychosocial stress might disturb remyelination though IL-6 and its relevant brain functions in patients with aberrant myelination such as MS, schizophrenia and mood disorders.Accumulating findings have shown that psychosocial stress is implicated in the pathobiology of multiple sclerosis. Most of studies regarding psychosocial stress have focused on the onset or relapse of the symptoms, aiming to examine the effects on the “demyelination”. In this study, we sought to investigate whether psychosocial stress affects remyelination, not demyelination since our previous study indicated that psychosocial stress substantially changes myelination only during myelin-developing phase. In order to accomplish this, myelin in the medial prefrontal cortex (mPFC) was depleted with cuprizone and the effects of subsequent social experience on remyelination were evaluated. Interestingly, myelination in the mPFC were severely impaired in socially isolated mice after myelin depletion. We also found that social isolation for 4 weeks increased the levels of interleukin-6 (IL-6) in the mPFC. Moreover, insufficient remyelination in the mPFC of socially isolated mice after myelin-depletion was improved by the administration of IL-6 inhibitor. To validate of the effects of IL-6 on myelination, we performed a neuron-oligodendrocyte co-culture and found that IL-6 treatment markedly interfered with myelination. This study, for the first time, provided direct evidence that social experience is associated with the extent of remyelination through IL-6 expression in mice. Together, these findings suggest that psychosocial stress might disturb remyelination though IL-6 and its relevant brain functions in patients with aberrant myelination such as MS, schizophrenia and mood disorders. PT686 Dextromethorphan-induced serotonin syndrome is via up-regulation of 5-HT1A receptors. Hai-Quyen Tran1, Duy-Khanh Dang1, Thu-Hien Thi Tu1,The-Vinh Tran1, Eun-Joo Shin1, Choon-Gon Jang2, Kuniaki Saito3, Toshitaka Nabeshima4, Hyoung-Chun Kim1 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200–701, Republic of Korea. 2Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea. 3Department of Medical Innovation, Fujita Health University Graduate School of Medical Sciences, Japan.4Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan. Abstract Objective: Serotonin syndrome is a serious adverse reaction characterized by a cluster of dose-related adverse effects that are due to increase serotonin (5-HT) concentrations in the central nervous system. Dextromethorphan (DM) has complex neuropharmacologic effects. It has been reported that high doses of DM produce serotonin syndrome in both human and animal models. 5-HT receptor activation is thought to contribute mainly to the serotonin syndrome in mice. In the present study, we have asked whether 5-HT receptor is involved in serotonin syndrome induced by DM. Methods: Mice were treated with WAY100635, a 5-HT1A receptor antagonist, or MDL11939, a 5-HT2A receptor antagonist, 30 min before DM administration. Scores of serotonin syndrome (i.e. reciprocal forepaw treading, lateral head-weaving, hind-limb abduction, tremor, Straub tail and flat body posture) were assessed during 30 min after DM. In addition, rectal temperature was measured 30 min after DM. Serotonin levels and 5-HT1A receptor mRNA expression were examined in the hypothalamus 2 h after DM.Objective: Serotonin syndrome is a serious adverse reaction characterized by a cluster of dose-related adverse effects that are due to increase serotonin (5-HT) concentrations in the central nervous system. Dextromethorphan (DM) has complex neuropharmacologic effects. It has been reported that high doses of DM produce serotonin syndrome in both human and animal models. 5-HT receptor activation is thought to contribute mainly to the serotonin syndrome in mice. In the present study, we have asked whether 5-HT receptor is involved in serotonin syndrome induced by DM. Methods: Mice were treated with WAY100635, a 5-HT1A receptor antagonist, or MDL11939, a 5-HT2A receptor antagonist, 30 min before DM administration. Scores of serotonin syndrome (i.e. reciprocal forepaw treading, lateral head-weaving, hind-limb abduction, tremor, Straub tail and flat body posture) were assessed during 30 min after DM. In addition, rectal temperature was measured 30 min after DM. Serotonin levels and 5-HT1A receptor mRNA expression were examined in the hypothalamus 2 h after DM. 50 | International Journal of Neuropsychopharmacology, 2016 Results: A high dose of DM significantly produced serotonin syndrome in mice. In addition, treatment with DM resulted in a significant increase in 5-HT1A receptor mRNA expression but not that of 5-HT2A receptor in the hypothalamus of mice. Furthermore, WAY100635, but not MDL11939, significantly attenuated increases in hypothalamic serotonin level, serotonergic behaviors and hypothermia induced by DM. Conclusion: Up-regulation of 5-HT1A receptor is essential for serotonin syndrome induced by DM in mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PT687 Dextromethorphan-induced serotonin syndrome requires activation of protein kinase Cd gene. Hai-Quyen Tran1, Duy-Khanh Dang, Huynh-Nhu Mai1, Bao-Trong Nguyen1, Eun-Joo Shin1, Choon-Gon Jang2, Kuniaki Saito3, Toshitaka Nabeshima4, Hyoung-Chun Kim1. 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200–701, Republic of Korea. 2Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea. 3Department of Medical Innovation, Fujita Health University Graduate School of Medical Sciences, Japan.4Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan. Abstract Objective: Our pilot study showed that 5-HT1A receptor mainly contributed to DM-induced serotonin syndrome in mice. Earlier reports suggested that 5-HT1A receptor can activate protein kinase C (PKC) in vitro. In the present study, we investigated whether the up-regulation of 5-HT1A receptor induced by DM requires specific induction of PKC isoform. Methods: Mice were pretreated with rottlerin, a pharmacological inhibitor of PKC-δ, 30 min before DM administration. Scores of serotonin syndrome (i.e. reciprocal forepaw treading, lateral head-weaving, hind-limb abduction, tremor, Straub tail and flat body posture) were assessed during 30 min after DM. In addition, rectal temperature was measured 30 min after DM. Serotonin levels and 5-HT1A receptor mRNA expression were examined in the hypothalamus 2 h after DM. Results: A high dose of DM resulted in a specific induction of PKC-δ out of PKC-α, PKC-β1, PKC-β2, PKC-ξ, PKC-δ in the hypothalamus of mice. Rottlerin significantly attenuated serotonergic behaviors induced by DM. In addition, rottlerin protected increases in 5-HT1A receptor mRNA expression and serotonin level induced by DM in wild-type mice. Consistently, genetic inhibition of PKC-δ protected serotonergic behaviors and increases in serotonin level, mRNA expression of 5-HT1A receptor induced by DM. Conclusion: Endogenous PKC-δ gene mediates serotonin syndrome induced by DM in mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea].Objective: Our pilot study showed that 5-HT1A receptor mainly contributed to DM-induced serotonin syndrome in mice. Earlier reports suggested that 5-HT1A receptor can activate protein kinase C (PKC) in vitro. In the present study, we investigated whether the up-regulation of 5-HT1A receptor induced by DM requires specific induction of PKC isoform. Methods: Mice were pretreated with rottlerin, a pharmacological inhibitor of PKC-δ, 30 min before DM administration. Scores of serotonin syndrome (i.e. reciprocal forepaw treading, lateral head-weaving, hind-limb abduction, tremor, Straub tail and flat body posture) were assessed during 30 min after DM. In addition, rectal temperature was measured 30 min after DM. Serotonin levels and 5-HT1A receptor mRNA expression were examined in the hypothalamus 2 h after DM. Results: A high dose of DM resulted in a specific induction of PKC-δ out of PKC-α, PKC-β1, PKC-β2, PKC-ξ, PKC-δ in the hypothalamus of mice. Rottlerin significantly attenuated serotonergic behaviors induced by DM. In addition, rottlerin protected increases in 5-HT1A receptor mRNA expression and serotonin level induced by DM in wild-type mice. Consistently, genetic inhibition of PKC-δ protected serotonergic behaviors and increases in serotonin level, mRNA expression of 5-HT1A receptor induced by DM. Conclusion: Endogenous PKC-δ gene mediates serotonin syndrome induced by DM in mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PT688 PKCδ gene facilitates cognitive impairment induced by low doses of methamphetamine (MA) in mice The-Vinh Tran1, Hai-Quyen Tran1, Thu-Hien Thi Tu1, Eun-Joo Shin1, Choon-Gon Jang2, Kiyofumi Yamada3, Toshitaka Nabeshima4, HyoungChun Kim1 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200–701, Republic of Korea; 2Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; 3Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine; 4Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan Abstract Objective: We suggested that the cognitive impairment induced by repeated MA treatment in mice is a useful model of the cognitive deficits in schizophrenia and MA psychosis. We also demonstrated that minocycline, an antibiotic possessing antiinflammatory activity, improves cognitive impairment induced by MA. It is well-known that protein kinase C (PKC) mediates neuroinflammation. Therefore, we investigated a specific role of PKC in response to cognitive impairment induced by MA. Method: To achieve a better understanding whether PKC expression can be altered by repeated treatment with MA. We examined changes in the expression of PKCα, PKCβ1, PKCβ2, PKCζ, and PKCδ in the prefrontal cortex (PFC) after the final MA treatment. Because PKCδ expression is selectively increased after the last MA, we applied PKCδ knock-out (KO) mice in this study. We evaluated relationship between novel object recognition test (NORT), phosphorylation of extracellular signal-regulated kinase 1⁄2 (p-ERK1⁄2), and phosphorylation of PKCδ (p-PKCδ) in the PFC. Result: Repeated treatment with MA resulted in cognitive impairment as evaluated by NORT. This effect lasted, at least, for 28 days after the final MA treatment. Correlation study indicated that cognitive impairment parallels p-PKCδ expression. P-ERK1⁄2 expression increased in the mice exposed to the novel objects in the absence of MA, but it was decreased in the presence of MA. Genetic inhibition of PKCδ attenuated MA-induced decrease in p-ERK1⁄2 expression. Posttreatment with antipsychotic clozapine significantly protected cognitive impairment and alteration in p-ERK1⁄2 and p-PKCδ. Conclusion: PKCδ gene is an endogenous neuropsychostimulant for behavioral side effects and cognitive impairment induced by MA. Interestingly, clozapine positively modulated p-ERK1⁄2 and p-PKCδ induced by MA in the PFC of mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea].Objective: We suggested that the cognitive impairment induced by repeated MA treatment in mice is a useful model of the cognitive deficits in schizophrenia and MA psychosis. We also demonstrated that minocycline, an antibiotic possessing antiinflammatory activity, improves cognitive impairment induced by MA. It is well-known that protein kinase C (PKC) mediates neuroinflammation. Therefore, we investigated a specific role of PKC in response to cognitive impairment induced by MA. Method: To achieve a better understanding whether PKC expression can be altered by repeated treatment with MA. We examined changes in the expression of PKCα, PKCβ1, PKCβ2, PKCζ, and PKCδ in the prefrontal cortex (PFC) after the final MA treatment. Because PKCδ expression is selectively increased after the last MA, we applied PKCδ knock-out (KO) mice in this study. We evaluated relationship between novel object recognition test (NORT), phosphorylation of extracellular signal-regulated kinase 1⁄2 (p-ERK1⁄2), and phosphorylation of PKCδ (p-PKCδ) in the PFC. Result: Repeated treatment with MA resulted in cognitive impairment as evaluated by NORT. This effect lasted, at least, for 28 days after the final MA treatment. Correlation study indicated that cognitive impairment parallels p-PKCδ expression. P-ERK1⁄2 expression increased in the mice exposed to the novel objects in the absence of MA, but it was decreased in the presence of MA. Genetic inhibition of PKCδ attenuated MA-induced decrease in p-ERK1⁄2 expression. Posttreatment with antipsychotic clozapine significantly protected cognitive impairment and alteration in p-ERK1⁄2 and p-PKCδ. Conclusion: PKCδ gene is an endogenous neuropsychostimulant for behavioral side effects and cognitive impairment induced by MA. Interestingly, clozapine positively modulated p-ERK1⁄2 and p-PKCδ induced by MA in the PFC of mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PT689 Utilization of Psychotic Drugs in Taiwan: An Overview of Outpatient Sector in 2010 Wei-Chen Lina,b,c, Wen-Han Changa, Ya-Mei Baia,b, Cheng-Ta Lia,b,c, Mu-Hong Chena,b, Tung-Ping Sua,b,c,d aDepartment of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; bDivision of Psychiatry, Faculty of Medicine, National YangMing University, Taipei, Taiwan; cInstitute of Brain Science, National Yang-Ming University, Taipei, Taiwan; dDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan Abstract Objective: Pharmacological treatment in mental disorder has been getting popular over decades in Taiwan. Our aims are 1) to survey the utilization of psychotropic drugs in outpatient psychiatric services, 2) to know the difference of antipsychotic drugs prescriptions among psychiatrists and non-psychiatrists. Methods: The sampling datasets from the Taiwan National Health Insurance Research Data base (NHIRD) served as data sources. We performed a survey comprising 886,219 participantsObjective: Pharmacological treatment in mental disorder has been getting popular over decades in Taiwan. Our aims are 1) to survey the utilization of psychotropic drugs in outpatient psychiatric services, 2) to know the difference of antipsychotic drugs prescriptions among psychiatrists and non-psychiatrists. Methods: The sampling datasets from the Taiwan National Health Insurance Research Data base (NHIRD) served as data sources. We performed a survey comprising 886,219 participants